CDK4/6 inhibitor PD-0332991 suppresses hepatocarcinogenesis by inducing senescence of hepatic tumor-initiating cells.

Chen, Miaomiao; Chen, Wenjian; Sun, Shiwen; Lu, Yanli; Wu, Guoxiu; Xu, Hongyu; Yang, Huiru; Li, Chong; He, Weizhi; Xu, Mingyang; Li, Xiuhua; Jiang, Dong; Cai, Yongchao; Liu, Changcheng; Zhang, Wencheng; He, Zhiying

Chen, Miaomiao; Chen, Wenjian; Sun, Shiwen; Lu, Yanli; Wu, Guoxiu; Xu, Hongyu; Yang, Huiru; Li, Chong; He, Weizhi; Xu, Mingyang; Li, Xiuhua; Jiang, Dong; Cai, Yongchao; Liu, Changcheng; Zhang, Wencheng; He, Zhiying.

Afiliación

Chen M; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Chen W; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Sun S; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Lu Y; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Wu G; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Xu H; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Yang H; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Li C; Zhoupu Community Health Service Center of Pudong New Area, Shanghai, China.
He W; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Xu M; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Li X; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Jiang D; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Cai Y; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Liu C; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
Zhang W; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai
He Z; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai

J Adv Res ; 2024 Aug 31.

Article en En | MEDLINE | ID: mdl-39218249

ABSTRACT

ABSTRACT

INTRODUCTION:

Owing to the limited treatment options for hepatocellular carcinoma (HCC), interventions targeting pre-HCC stages have attracted increasing attention. In the pre-HCC stage, hepatic tumor-initiating cells (hTICs) proliferate abnormally and contribute to hepatocarcinogenesis. Numerous studies have investigated targeted senescence induction as an HCC intervention. However, it remains to be clarified whether senescence induction of hTICs could serve as a pre-HCC intervention.

OBJECTIVES:

This study was designed to investigate whether senescence induction of hTICs in the precancerous stage inhibit HCC initiation. METHODS AND

RESULTS:

HCC models developed from chronic liver injury (CLI) were established by using Fah-/- mice and N-Ras + AKT mice. PD-0332991, a selective CDK4/6 inhibitor that blocks the G1/S transition in proliferating cells, was used to induce senescence during the pre-HCC stage. Upon administration of PD-0332991, we observed a significant reduction in HCC incidence following selective senescence induction in hTICs, and an alleviation liver injury in the CLI-HCC models. PD-0332991 also induced senescence in vitro in cultured hTICs isolated from CLI-HCC models. Moreover, RNA sequencing (RNA-seq) analysis delineated that the "Cyclin D-CDK4/6-INK4-Rb" pathway was activated in both mouse and human liver samples during the pre-HCC stage, while PD-0332991 exhibited substantial inhibition of this pathway, thereby inducing cellular senescence in hTICs. Regarding the immune microenvironment, we demonstrated that senescent hTICs secrete key senescence-associated secretory phenotypic (SASP) factors, CXCL10 and CCL2, to activate and recruit macrophages, and contribute to immune surveillance.

CONCLUSION:

We found that hTICs can be targeted and induced into a senescent state during the pre-HCC stage. The SASP factors released by senescent hTICs further activate the immune response, facilitating the clearance of hTICs, and consequently suppressing HCC occurrence. We highlight the importance of pre-HCC interventions and propose that senescence-inducing drugs hold promise for preventing HCC initiation under CLI.

Palabras clave

CDK4/6 inhibitors; Cellular senescence; Cyclin D-CDK4/6-INK4-Rb pathway; HCC; Tumor-initiating cells

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Adv Res Año: 2024 Tipo del documento: Article Pais de publicación: Egipto